A greater understanding of individual differences in the neurobiology of tobacco use is integral to developing more effective tobacco interventions. Understanding these individual differences would facilitate matching individuals with a specific biological vulnerability (e.g., genetic variation that alters nicotine receptor function), to an intervention that targets that vulnerability (e.g., a medication that targets nicotinic receptor function, like varenicline). Our previous studies clearly indicate the critical role of specific genetic variation in the gene (CHRNA4) that codes for the 4 subunit of the 42 nicotinic receptor. This proposed research will extend our previous work by testing whether this genetic variation influences brain activation in response to smoking cues and influences the clinical effects of varenicline. Specifically, the first aim is to determine whether a functional single nucleotide polymorphism (SNP) in the CHRNA4 gene influences the acute effects of smoking and influences mesocorticolimbic activation in response to smoking cues. The second aim is to replicate the finding that varenicline increases abstinence and identify brain based measures that predict treatment outcome. The third aim is to determine whether the CHRNA4 SNP moderates the effects of varenicline on abstinence. To accomplish these aims, 216 treatment seeking smokers will participate in a 12 week, placebo controlled trial of varenicline with a neuroimaging assessment at baseline and behavioral assessments at baseline, 2, 6, and 12 weeks and a 6 month follow-up. The proposed research on genetic variation that predicts responses to varenicline is expected to have significant clinical implications.